Developing a database and geostatistical methods to study the epidemiology of PIBD

Inflammatory bowel diseases (IBD) are chronic idiopathic disorders that cause inflammation of the gastrointestinal tract. These chronic conditions affect over 2.5 million people in Europe alone, with a direct healthcare cost of €4.6-5.6 billion annually (Jairath, V., & Feagan, B. G., 2020). While the IBD burden has increased rapidly in recent decades in most Western countries, this rate of increase seems to be slowing down. Conversely, newly industrialised regions are currently seeing a spike in incidence rates. To date, paediatric inflammatory bowel disease (PIBD) incidence and prevalence information can be found in just over 100 publications that cite figures from 35 different countries reporting significant spatial and temporal variations with a few clear patterns. The current literature often combines mostly heterogeneous information from studies using various methods with limited spatiotemporal coverage. Despite over 200 genetic loci being linked to IBD, only 10-15% of the disease risk is attributed to genetic factors (Shouval, D. S., & Rufo, P. A., 2017). Therefore, we hypothesised that certain external risk factors might be linked to developing PIBD, similar to other chronic diseases, such as rheumatoid arthritis and asthma. In the paediatric population specifically, given the limited exposures and co-morbidities compared to the adult population, environmental and socio-economic factors may play a particularly significant role in the development of the disease. In this prospective study, I developed several methods for collecting, processing and analysing PIBD incidence and prevalence data. The main six aims of the project were the following: i. Develop and establish methods to collect international PIBD data uniformly ii. Organise and prepare these data iii. Develop the project-specific analytical methods iv. Estimate the incidence and prevalence of the disease v. Collect and prepare the risk factors data from multiple international datasets vi. Study the effects of these factors on the disease epidemiology The methods involved the development of two separate databases that were created to collect clinical and epidemiological data, refining the calculation of disease incidence by adjusting for different reporting centres, and compiling a novel dataset of suspected risk factors for the disease while focusing on interpolated pollutants. After designing an automated Electronic Data Capturing system (EDC), I conducted five annual data collection rounds, gathering over 500 responses from 140 PIBD experts worldwide. The estimation and mapping of the incidence and prevalence revealed significant spatiotemporal trends with recent years and latitudes closer to the north presenting a significant positive correlation with the incidence. The risk factors were extracted from validated sources and used as predictors after being processed and transformed using various computationally intensive methods. The processing and harmonisation of the predictor data, which involved handling misaligned information formats and diverse types of territorial units, was one of the most challenging aspects of this project. The final geostatistical analysis of the PIBD incidence revealed that the most significant findings were the particulate matter (PM10) and carbon monoxide, followed by carbon dioxide and chlorine with inorganic compounds (HCl). The latter pollutant is a novel finding as it has not been reported previously in the literature. Further geostatistical analysis of the phenotype ratio of the disease, Crohn’s and Ulcerative colitis, revealed the importance of sun exposure, population density and three pollutants from the broader family of volatile organic compounds in the development of the disease. The PIBD phenotype ratio analysis was repeated based on the environmental questionnaire of the inception cohort clinical study and showed that the patient demographics, the preferred source of water, and surprisingly, contact with certain animals were also potentially important predictors of the type of diagnosis. Our incidence and prevalence findings are consistent with most of the partially established spatiotemporal patterns of PIBD in the literature. This provides validation of the methods used and strengthens our findings. The statistical methods developed in this project were based on several spatial interpolation models, disease mapping techniques, Linear Mixed-effects Models (LMM), spatial regression, model fit diagnostics and the development of study-specific functions used to adjust the reported data. The spatial interpolation methodology was optimised with a series of simulations, while the LMM and spatial regression were employed to address the autocorrelation in our data. The following chapters provide detailed insights into the methods and results of this thesis followed by a discussion of our findings

The incidence and characteristics of venous thromboembolisms in paediatric-onset inflammatory bowel disease; a prospective international cohort study based on the PIBD-SETQuality Safety Registry.

BACKGROUND & AIMS: Guidelines regarding thromboprophylaxis for venous thromboembolisms (VTE) in children with inflammatory bowel disease (IBD) are based on limited paediatric evidence. We aimed to prospectively assess the incidence of VTE in paediatric-onset IBD (PIBD), characterize PIBD patients with VTE, and identify potential IBD-related risk factors. METHODS: From October 2016 till September 2020, paediatric gastroenterologists prospectively replied to the international Safety Registry, monthly indicating whether they had observed a VTE case in a patient <19 years with IBD. IBD details (type, Paris classification, clinical and biochemical disease activity, treatment) and VTE details (type, location, treatment, outcome) were collected. To estimate the VTE incidence, participants annually reported the number of PIBD patients, data source and catchment area of their center. A systematic literature review and meta-analysis was performed to calculate the VTE incidence in the general paediatric population. RESULTS: Participation of 129 PIBD centers resulted in coverage of 24,802 PIBD patients. Twenty cases of VTE were identified (30% Crohn's disease). The VTE incidence was 3.72 [95%CI 2.27 - 5.74] per 10,000 person-years, 14-fold higher than in the general paediatric population (0.27 [95%CI 0.18-0.38], p<0.001). Cerebral sinus venous thrombosis was most frequently reported (50%). All but one patient had active IBD, 45% were using steroids and 45% hospitalized. No patient received thromboprophylaxis, whereas according to current PIBD guidelines, this was recommended in 4/20 patients. CONCLUSION: There is an increased risk of VTE in the PIBD population compared to the general paediatric population. Awareness of VTE occurrence and prevention should be extended to all PIBD patients with active disease, especially those hospitalized

High Impact of Pediatric Inflammatory Bowel Disease on Caregivers' Work Productivity and Daily Activities: An International Prospective Study

To evaluate the longitudinal evolution of work productivity loss and activity impairment in caregivers of children with inflammatory bowel disease (IBD). We also evaluated the associations between these impairments, IBD-related factors, and caregivers’ health-related quality of life (HRQOL) and estimated the indirect costs related to work absenteeism. Study design Since January 2017, children with newly diagnosed IBD were enrolled prospectively in the Pediatric Inflammatory Bowel Disease Network for Safety, Efficacy, Treatment and Quality improvement of care study. The impact of pediatric-onset IBD on caregivers' socioeconomic functioning (work and daily activities) and HRQOL was assessed using the Work Productivity and Activity Impairment for caregivers questionnaire and the European Quality of Life Five Dimension Five Level questionnaire, at diagnosis and 3 and 12 months of age. Generalized estimating equation models were applied to evaluate outcomes longitudinally, adjusted for IBD type, disease activity, and child's age at diagnosis. Results Up to July 2021, 491 children with IBD were eligible for analysis of caregivers' Work Productivity and Activity Impairment questionnaire. At diagnosis, the mean caregivers' employment rate was 78.4%; the adjusted mean work productivity loss was 44.6% (95% CI, 40.2%-49.0%), and the adjusted mean activity impairment was 34.3% (95% CI, 30.8%-37.7%). Work productivity loss and activity impairment significantly decreased over time and were associated with disease activity, but not with IBD type or child's age. Caregivers' HRQOL was associated with both impairments. Costs related to work absenteeism were at least €6272 ($7276) per patient during the first year after diagnosis. Conclusions Caregivers of children with IBD experience significant impairments in work and daily activities, especially at diagnosis. The impact decreases thereafter and is associated with disease activity and caregivers’ HRQOL. Work absenteeism results in high indirect costs

Improved Clinical Outcomes With Early Anti-Tumour Necrosis Factor Alpha Therapy in Children With Newly Diagnosed Crohn's Disease: Real-world Data from the International Prospective PIBD-SETQuality Inception Cohort Study.

BACKGROUND AND AIMS: Treatment guidelines for paediatric Crohn's disease [CD] suggest early use of anti-tumour necrosis factor alpha [anti-TNFα] in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF [<90 days after diagnosis] and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission [SSFR] without treatment intensification [specified as SSFR*] and sustained steroid-free mild/inactive disease without treatment intensification [specified as SSFMI*]. Penalised logistic regression model-based standardisation was applied to estimate the relative risks [RR] of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients, based on presence of predictors of poor outcome [POPOs] and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2-15.3]) were enrolled, with 135 [41%] receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* [30% vs 14%, p <0.001] and SSFMI* [69% vs 33%, p <0.001], with RRs of 2.95 [95% CI 1.63-5.36] and 4.67 [95% CI 2.46-8.87], respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared with mild/inactive disease at diagnosis (5.50 [95% CI 2.51-12.05] vs 2.91 [95% CI 0.92-9.11]), and those with any POPO compared with no POPO (5.05 [95% CI 2.45-10.43] vs 3.41 [95% CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study

INTRODUCTION: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors. METHODS AND ANALYSIS: In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease &lt;18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent's smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up. ETHICS AND DISSEMINATION: Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications. TRIAL REGISTRATION NUMBER: NCT03571373

TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease

This work was funded by the Diabetes Research and Wellness Fund. WA is in receipt of an MRC New Investigator Award

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study

INTRODUCTION: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors. METHODS AND ANALYSIS: In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent's smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up. ETHICS AND DISSEMINATION: Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications. TRIAL REGISTRATION NUMBER: NCT03571373